Spatial‐temporal modulation in radiation therapy

In his treaty Physics and Philosophy, the renowned physicist Sir James Jeans started with the following opening statement:1 “Science usually advances by a succession of small steps, through a fog in which even the most keen-sighted explorer can seldom see more than a few paces ahead. Occasionally the fog lifts, an eminence is gained, and awider stretch of territory can be surveyed – sometimes with startling results.” Jeans, as he crafted that statement, had in mind the development of modern physics in the early 1900s. Built upon the foundation of Newtonian and Maxwellian theories, the physics community was looking for a new path in physics to resolve the critical challenges of certain anomalies revealed in a collection of experiments. As if a blessing from the sky, the younger generation of physicists were able to strike major breakthroughs by following the leads revealed in effects – that were “tiny and subtle”, sometimes even considered “non-essential” – by some of the established authorities of the day. However, in science, often when the fog has lifted, the new insights are not always captured or recognized immediately. An example that comes to mind is the perihelion orbit of the planetMercury, described as a tiny “anomalous” effect when it was first recognized in 1859, but then, it would take the insight of an Einstein to point out its significance half a century later, with his revolutionary new theory of gravity. As we examine the history of medicine, specific to the development of radiation therapy (RT), it appears that as a scientific community we have come to a cross-road, similar to the Rubicon traversed by classical physics in the early part of last century. In a general sense, the critical-target theory of traditional radiobiology has been, to a great degree, guiding the field of RT since its inception. With the concepts of the 4Rs being established to form its biological backbone, RT has firmly established itself as one of the indispensable pillars of cancer treatment management – with both hyperand hypo-fractionation strategies being the gold standards of clinical practice. Historically, technical advances inRThave centered on the improvement of dose distribution – in terms of conformity to the targets – while minimizing normal tissue exposure, and the delivery’s accuracy and efficiency of treatments. The impressive success and advances in modern RT are, however, accompanied by the frustrations of RT’s limitations in the apparent confinement to local control, and in the further reduction of normal tissue toxicities. To overcome these limitations, we have been seeking signs and indications that might point to newdirections for radically improving the therapeutic ratio, where this